Higano Examines Emerging Role of PARP Inhibitors in mCRPC

Celestia Higano, MD, FACP

PARP inhibitors have not made the same headway in metastatic castration-resistant prostate cancer (mCRPC) as they have in ovarian and breast tumors, but recent data suggest that the class of drugs could play a role in patients with mCRPC who have certain DNA repair defects, said Celestia Higano, MD.

For example, preliminary data from the phase II single-arm TRITON2 trial showed that treatment with rucaparib (Rubraca) resulted in a 44% confirmed objective response rate (ORR) by investigator assessment in patients with mCRPC who harbor BRCA1/2 mutations.¹ There was also a 51% confirmed prostate-specific antigen response in those who received the PARP inhibitor.

Based on these positive findings, the FDA granted a breakthrough therapy designation to rucaparib in October 2018 for the treatment of patients with BRCA1/2-mutated mCRPC. The phase III TRITON3 trial (NCT02975934), which will compare rucaparib with physician’s choice of therapy in this patient population, is currently accruing.

In addition, data from the ongoing phase II GALAHAD trial (NCT02854436) presented at the 2019 Genitourinary Cancers Symposium suggested that single-agent niraparib (Zejula) could be a beneficial option for patients with biallelic BRCA1/2 mutations. In the study, the composite response rate in those who received the agent was 62.1%, and the ORR was 37.5%.²

OncLive: What data supported the emergence of PARP inhibitors in prostate cancer?

What percentage of patients with prostate cancer have DNA repair defects?

In an interview with OncLive, Higano, a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center and a professor in the Department of Medicine and Urology at the University of Washington and Seattle Cancer Care Alliance, discussed the potential for PARP inhibitors in patients with mCRPC, as well as the role of darolutamide in nonmetastatic disease.Higano: The interesting thing is that we've seen some scant, very intriguing data in prostate cancer. There are a lot more data with PARP inhibitors in other cancers. However, in prostate cancer, we first became sensitized to the importance of PARP inhibitors in a study that was published several years ago in the New England Journal of Medicine. In that study, they found a very high response rate—approximately 88%—in patients who had DNA repair defects compared with those who did not. That particular study really got our attention and, all of a sudden, opened the door for PARP inhibitors in prostate cancer.It's not common, but it's not that rare either. As a matter of fact, there are more people with these DNA repair problems than we previously appreciated. One of the reasons is that we were just looking at the tissue of patients who were diagnosed with early-stage prostate cancer. In that case, there was a smaller percentage.

Keeping that in mind, is genetic testing being performed on all patients?

What are the next steps for research with PARP inhibitors?

Do PARP inhibitors fit into the precision medicine approach we are now seeing used in many tumor types?

However, when we actually looked at men with mCRPC, we found that the percentage tripled and maybe even quadrupled. It is probably somewhere around 25%. There are some lower figures, but it depends on what mutations you're looking at. There is a pretty decent amount of men who will be susceptible to drugs that target DNA repair.In prostate cancer, we are still trying to understand this. In academic institutions, many of us are fairly routinely checking for germline mutations in our patients with metastatic disease—that means looking at the DNA they were born with. We have to distinguish between that and somatic testing, where we are looking at the DNA of the tumor itself. They are 2 different things, and there is still some level of misunderstanding about those 2 sets of testing. Genetic testing is not standard of care by any means, but it is actually referenced in the new National Comprehensive Cancer Network guidelines. It's not in widespread use because we are still trying to grapple with how we use the data.There are several PARP inhibitors being studied, and many of them have been FDA approved for other malignancies, mainly breast and ovarian cancers. We are now in both phase II and III studies evaluating the use of single-agent PARP inhibitors after chemotherapy in patients with metastatic disease, or before chemotherapy, like we are seeing in the TRITON3 trial. We are still trying to figure out where these agents fit into the treatment paradigm and what their benefits are.This is an interesting thing because we don't know. If you go back to the original article published in New England Journal of Medicine, it wasn't as if patients without DNA repair didn't have any responses [to PARP inhibitors]. A small percentage, about 6%, actually did respond to those agents.

What data presented at the 2019 Genitourinary Cancers Symposium did you find practice changing in the prostate cancer space?

What are the most concerning adverse events associated with enzalutamide and apalutamide that would provide rationale to explore another drug?

These drugs may also have roles in terms of transcription of factors that are important for blocking the androgen receptor. As such, it may be that PARP inhibitors may have a dual role in helping us combat prostate cancer.There was the use of darolutamide for nonmetastatic CRPC, which adds a third drug to the other 2 that we already have: enzalutamide (Xtandi) and apalutamide (Erleada). Darolutamide is not FDA approved yet, but it has the potential of being different from the other 2 drugs because it has a different molecular structure. These drugs are sort of cousins to each other. The different structure may result in a different toxicity profile for darolutamide. It already seems like the toxicity profile is different, although the studies are not comparing these drugs head-to-head. We can only compare the 3 separate studies, which isn't a very legitimate comparison.Enzalutamide and apalutamide both cross the blood-brain barrier. I wouldn't say darolutamide doesn't at all, but it does so much less. The thought is that this may be partially responsible for some of the toxicities like fatigue, weakness, falls, etc. It's hard to explain some of the things these drugs do to the CNS, but anyone who sees patients on these drugs knows that sometimes patients complain of bizarre dreams or strange thoughts. If these things are related to those drugs crossing into the brain, it may not be as apparent with darolutamide. We aren't going to know the answer to this though. They all look identical in terms of clinical outcome with metastasis-free survival. However, whether darolutamide is really superior to these 2 agents in terms of toxicity, [is something] we are not going to know this for a long time.

References

1. Abida W, Bryce AH, Vogelzang NJ, et al. Preliminary results from TRITON2: a phase 2 study of rucaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract PD793.
2. Smith MR, Sandhu SK, Kelly WK, et al. Phase II study of niraparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): preliminary results of GALAHAD. J Clin Oncol. 2019;37(suppl 7; abstr 202). doi: 10.1200/JCO.2019.37.7_suppl.202.